PPAR-γ agonist attenuates renal interstitial fibrosis and inflammation through reduction of TGF-β

Abstract

Thiazolidinediones (TZDs), synthetic peroxisome proliferator-activated receptor (PPAR)-g ligands, have a central role in insulin sensitization and adipogenesis. It has been reported that TZDs exert protective effects in both diabetic and nondiabetic models of renal disease, although the exact mechanism is not well understood. In particular, only a few studies have reported the renoprotective effects of TZDs in nondiabetic models of tubulointerstitial fibrosis and inflammation. Therefore, we investigated the anti-fibrotic and anti-inflammatory effects of the TZD troglitazone in the mouse model of unilateral ureteral obstruction (UUO). C57BL/6J mice underwent UUO and were studied after 3 and 7 days. Animals were divided into three groups and received control vehicle, troglitazone (150 mg/kg per day) or troglitazone (300 mg/kg per day) by gavage. Kidneys were harvested for morphological, mRNA and protein analysis. Reversetranscriptase-PCR was used to assess the expression of transforming growth factor-b1 (TGF-b1) and the TGF-b1 type I receptor (TGFbR-I). Protein expression was assessed by western blotting (TGFbR-I) and immunostaining (TGFbR-I, a-smooth muscle actin (a-SMA), type I collagen (collagen I), F4/80, and proliferating cell nuclear antigen (PCNA)). The expression of a-SMA, collagen I, and F4/80 was decreased in mice treated with troglitazone compared with the control group. The numbers of PCNA-positive interstitial cells were decreased in mice treated with troglitazone. TGF-b1 mRNA and TGFbR-I mRNA and protein expression were decreased in the group treated with troglitazone compared with the control group. The beneficial effects of troglitazone treatment were also dose dependent. PPAR-g agonist significantly reduced TGF-b and attenuated renal interstitial fibrosis and inflammation in the model of UUO.

PPAR-γ agonist rosiglitazone protects peritoneal membrane from dialysis fluid-induced damage

“…9 PPAR-g agonists have both anti-diabetic and anti-inflammatory properties [20][21][22][23][24][25][26][27] and they have been associated with anti-fibrotic effects in several experimental models and in patients. [28][29][30][31][32] However, the potential of PPAR-g agonists to act as therapeutic agents to ameliorate peritoneal membrane damage, as well as their mechanisms of action, have not yet been explored in depth. 33,34 In this study, we show that oral administration of the PPAR-g agonist RSG ameliorates the peritoneal damage induced by PD fluids exposure in a newly developed mouse PD model.…”

“…[22][23][24][25][26][27] Probably as a consequence of these multiple anti-inflammatory actions, PPAR-g ligands have demonstrated anti-fibrotic effects in several experimental models, including diabetic and nondiabetic chronic kidney diseases. [28][29][30][31] It has been described that PPAR-g agonists improve renal function in patients with incipient diabetic nephropathy. 32 However, the potential protective effects for the peritoneal membrane of agents that activate PPARg have not been explored in depth.…”

Klotho Inhibits Transforming Growth Factor-β1 (TGF-β1) Signaling and Suppresses Renal Fibrosis and Cancer Metastasis in Mice

“…Immunohistochemistry-Paraffin sections of the kidney were stained with antibodies against ␣SMA (Sigma) and collagen-1 (Abcam, Cambridge, MA) as previously described (28). The signal intensity of collagen-1 was quantified using ImageJ software as previously described (28).…”

Inhibiting nonmuscle myosin II impedes inflammatory infiltration and ameliorates progressive renal disease

“…Male Sprague-Dawley rats weighing 200-250 g were subjected to UUO surgery using an established procedure. 31 In essence, complete ureteral obstruction was performed under general anesthesia by double-ligating the left ureter using 4-0 silk after a midline abdominal incision. Sham-operated animals had their ureters exposed, manipulated but not ligated.…”